The Seattle Cancer Consortium (SCC) Breast SPORE application, led by Drs. Peggy Porter and Martin Mac Cheever, brings together clinical and laboratory researchers from the Fred Hutchinson Cancer Research Center (FHCRC) and the University of Washington (UW) with a goal to positively impact breast cancer prevention, detection, treatment and care of women who have, or are at risk for, the disease. To achieve that goal, we will carry out strategic research in highly translational projects, develop new research directions as the SPORE progresses, and sponsor new investigators-those starting their careers and those with established careers newly focusing on breast cancer. The investigators in this SPORE view the highly variable response of breast cancers to current therapies as a manifestation of the genotypic and phenotypic heterogeneity of the disease. Therefore, the initial projects on the SPORE will focus on the supposition that targeted treatments need to be focused on the appropriate tumor type. The four major research projects proposed for the Seattle SPORE expand on this theme. Two of the projects are initiated with clinical trials and a focused bed-side-to-bench translational approach. Three of the projects are focused on gaining insight into resistance to therapy and eventually defining what targeted therapies are needed to treat resistant tumors. Project 1 will apply basic discovery of p27kip1 cell cycle regulation in breast cancer to predict mortality and response to therapy. Project 2 will use exquisitely specific and engineered central memory T cells to target abnormally expressed tumor-associated proteins with vaccines and therapy. Project 3 will determine the biological basis for a breast imaging metabolism/perfusion mismatch profile that predicts poor prognosis and poor response to systemic therapy. Project 4 will draw on a well-characterized population-based cohort to identify specific DNA damage pathway biomarkers that could prevent the over, or under, treatment of women with breast cancer. Together, these four projects afford both short- and long-term translational rewards and potential for new discoveries that will impact important aspects of breast cancer care. The SPORE is enhanced by a Developmental Research Program (DRP), a Career Development Program (CDP) and four supporting Cores: Leadership, Specimen Acquisition and Pathology, Clinical, and Biostatistics. These elements, along with the existing highly interactive and interdisciplinary environment and outstanding institutional support for breast cancer research in the FH/UW Cancer Consortium, ensure a successful translational SPORE program in breast cancer.